The field of the invention is spectroscopy and, more particularly, systems for and method of spectroscopy for imaging erosion of biomaterials.
Biologically compatible and degradable materials have found an increased presence in clinical applications in recent years. Degradable biomaterials are less prone to complications associated with the long-term residence of foreign objects within a subject and can, for example, serve as platforms for structural stabilization, void filling, and tissue engineering. Beyond their use in implants and medical devices, degradable biomaterials are particularly valuable in drug delivery systems. Drugs are traditionally administered to a patient via injection or oral delivery, for example, using pills. These drug administration methods generally involve high drug concentrations that can lead to adverse side effects. To reduce complications associated with high drug concentrations, biomaterials such as biodegradable hydrogels can be employed to target drug delivery to a local region and provide controlled drug release over an extended time period. Hydrogel drug delivery systems, for example, can be employed to deliver pharmaceutical compounds including hormones, enzymes, antibiotics, and even cell suspensions. Also, endovascular stents may sometimes be coated with a polymer that releases a pharmaceutical to control restenosis of the vasculature. In such an application, it is often beneficial to promote endothelialization while controlling restenotic processes such as platelet aggregation and smooth muscle cell proliferation. Therefore, accurate characterization of in vivo biomaterial erosion, and its relationship to drug diffusion rates, is beneficial for the development of drug delivery systems that provide appropriate drug efflux to a region within a patient.
Biomaterial erosion can be followed in vitro using a number of techniques, most of which are inferential. Periodic sampling of biomaterial weight has traditionally served as a primary measure of erosion. However, this assumes that biomaterial weight change is strictly due to erosion and fails to account for biomaterial swelling, for example, due to solvent influx. Biomaterial swelling typically occurs in a non-linear fashion that is determined not only by solute properties, but by environmental conditions as well. Swelling of a biomaterial due to water uptake can continue for up to four days and peak swelling is typically followed by a period of rapid erosion and weight change. Because they produce different byproducts, different biomaterials can have a wide range effects on their local environment. Local environmental conditions, such as pH and local strain, can in turn affect biomaterial swelling and mass change occur. Since weight gain is often observable for a substantial period before weight loss, it can mask weight changes due to biomaterial erosion. Therefore, mass change cannot be relied upon as a sensitive marker of biomaterial erosion, especially when the biomaterial is placed within a subject whose in vivo environment is not as directly observable compared to an in vitro environment.
Methods for measuring biomaterial erosion in vitro using fluorescence spectroscopy have been proposed. For example, in a method described by Y. Yang, et al. (“On-line Fluorescent Monitoring of the Degradation of Polymeric Scaffolds for Tissue Engineering,” Analyst, 2005; (130):1502-1506), a fluorescent dye is attached to mesoporous silica particles, or “meso-particles.” Following fluorescent labeling, the meso-particles are mixed in a 5% polymer solution. As a result, the meso-particles become suspended in the polymeric biomaterial. The fluorescent intensity of the resultant biomaterial is then observed in an in vitro environment over a period of time in order to provide an indication of biomaterial erosion. However, the meso-particles disperse into the surrounding environment as the biomaterial degrades, thus reducing the efficacy of the measurements.
Loss of material integrity, structure, and eventually mass follow one another, but at different rates in the in vitro and in vivo domains. This is largely due to the complex interactions between an implanted biomaterial and its local environment. Some environmental conditions such as buffer type, buffer volume, pH, temperature, flow, and stresses can be approximated in vitro but do not necessarily represent the in vivo state. Other in vivo conditions, such as those associated with active inflammation, encapsulation, and similar reactions, cannot be recapitulated in vitro. Moreover, in vitro degradation analysis by traditional techniques often fails to distinguish between erosion, absorption, and degradation and does not always provide an accurate indication of in vivo performance, particularly when the biomaterials are formed into complex, three-dimensional structures. Accordingly, the utility of many degradable biomaterials for complex, implantable structures is severely limited when their behavior in vivo does not followed expectations based upon observed in vitro biodegradation kinetics. This mismatch between domains is illustrated by recent problems with bioerodible vascular stents. Traditional metal stents coated with permanent polymeric materials can have problems associated with long-term biocompatibility. It was hoped that bioerodible stents could provide a less problematic alternative. In clinical trials, however, bioerodible stents exhibited slower degradation and reduced biocompatibility than expected based upon extensive in vitro characterization and animal model examination. While they ultimately degrade, the stents' slow erosion necessitates long-term patient follow-up before it can be determined that the device is safe and stable. This behavior has strong regulatory implications and ultimately leads to the cancellation of the clinical trials.
Biomaterial degradation in vivo can be measured by tracking critical metabolites or byproduct appearance. For example, polyaminoacid breakdown can be followed by the appearance of amino acids. The reliability of such methods is based on the tenuous assumption that the appearance of byproducts, clearance in media, and analytic resolution are unaffected by the degradation of the biomaterial. Moreover, methods of mass or biochemical assay do not adequately account for the structural configuration of the biomaterial. Accordingly, blocks, drops, gels, and reticular networks of biomaterials of equal mass will typically degrade with significantly different kinetics.
Other methods for measuring biomaterial erosion in vivo employ the sequential examination of implanted candidate biomaterials in a group of animals. The animals are sacrificed at different points in time and biomaterial residues are detected and measured. One of the drawbacks of this method is that the implantation of a biomaterial in an animal is rarely indicative of the expected clinical application. Moreover, the detection of erosion is most often crude and mechanical rather than mechanistic. While these methods require the use of large numbers of animals, they estimate of the extent of biomaterial erosion and do not track factors such as biomaterial secretion and biomaterial migration from the implantation site.
The limitations of traditional in vivo biomaterial erosion measurements and the inability to properly relate biomaterial fate between the in vitro and in vivo domains significantly limits the utility of many biomaterials. It would therefore be desirable to have a noninvasive method for tracking biomaterial erosion in vivo.